The overall goal of this proposal is to better understand the roles of programmed cell death and protein turnover in the aging process. Towards this end we will focus our studies on analyses of these processes in the nervous system of Drosophila, a powerful molecular genetic model system. We will utilize a battery of genetic, biochemical, and cell biological approaches to address two major issues. The first is to understand the basis for functional interactions between Morgue, a novel F box/ubiquitin conjugase domain protein, and Effete/UbcD1, a highly conserved ubiquitin E2 conjugase. Both proteins have pro-cell death functions and can bind to and promote the turnover of DIAP1, an essential caspase inhibitor. Mutations in these genes exhibit strong genetic interactions and suggest that the two proteins function closely together to regulate nervous system cell survival and progression of flies through the life cycle. We will carefully analyze the cellular and behavioral phenotypes of various mutant combinations of these genes, as well as determine if the proteins act together in a ubiquitination complex. In addition we will analyze the ability of these proteins to promote cell death in Drosophila tissue and cultured mammalian cells. The second issue we address is to illuminate the relationship between cell death and aging in the Drosophila nervous system. Towards this end, we will document the patterns of cell death in wild type and mutant flies that exhibit altered lifespan and aging properties, elucidate the importance of nervous system cell death in influencing lifespan, and determine if neurons or glia exhibit altered abilities to die as they age. These studies will help illuminate the roles of the ubiquitin/proteasome pathway of protein turnover in programmed cell death and in turn, how changes in the propensity or ability of cells in the aging nervous system to die may influence nervous system function and life span. Significantly, studies in invertebrate model systems, such as the nematode Caenorhabditis elegans and fruit fly, Drosophila melanogaster, have provided invaluable insight into the genetic pathways and biochemical mechanisms of cell death and aging processes. As there exists many devastating late onset human neurological diseases, such as neural or glial cancers and neurodegeneration disorders, the results from these studies will| not only provide new insight into fundamental cellular processes, but will also have important biomedical relevance. [unreadable] [unreadable]